Dr Coombs on Noncovalent BTK Inhibitors in Relapsed/Refractory MCL

Catherine C. Coombs, MD, associate clinical professor, medicine, University of California, Irvine School of Medicine, discusses the need for, and mechanism of action of, noncovalent BTK inhibitors in patients with relapsed/refractory mantle cell lymphoma (MCL).

MCL is a rarer form of lymphoma, comprising approximately 6% of all lymphoma cases, and is most commonly observed in males, Coombs says. Various treatment options exist for patients with this disease depending on patient fitness and ECOG performance status, Coombs notes. Many first-line MCL treatment regimens continue to use chemotherapy with or without autologous stem cell transplant followed by rituximab (Rituxan) maintenance therapy, Coombs explains.

BTK inhibitors, including the newer-generation covalent BTK inhibitors acalabrutinib (Calquence) and zanubrutinib (Brukinsa), are effective and have become the standard of care for patients with relapsed MCL, according to Coombs. Before the advent of noncovalent BTK inhibitors, patients with MCL who progressed on a covalent BTK inhibitor had limited treatment options, and real-world outcomes in this patient population were poor, Coombs emphasizes.

In 2023, the FDA approved the noncovalent BTK inhibitor pirtobrutinib (Jaypirca) for the treatment of patients with relapsed/refractory MCL who have received 2 or more prior lines of therapy, including a BTK inhibitor. This regulatory decision was supported by findings from the single-arm, phase 1/2 BRUIN trial (NCT03740529), in which pirtobrutinib induced an overall response rate of 50% (95% CI, 41%-59%) in patients who received the agent at 200 mg daily (n = 120), including a 13% complete response rate and a 38% partial response rate.

Pirtobrutinib is effective in this patient population because it operates via a different binding mechanism than covalent BTK inhibitors, Coombs explains. The agent may stabilize BTK in an inactive conformation, inhibiting access to upstream kinases and residue Y551 phosphorylation, Coombs says. This mechanism can accordingly block scaffolding interactions that support kinase-independent BTK signaling, Coombs concludes.